About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

April 1, 2013

Novartis Loses the Glivec Patent Fight in India

Posted by Derek

This story is all over the news today, but it's my impression that most of the stories leave out crucial details. This is not just a big multinational drug company being put in its place by Indian courts, nor is it some crazy ruling with no basis in fact. Here's the story, as best I understand it.

Novartis has never had a patent for imatinib (Glivec/Gleevec) in India. I'm not completely sure why that is, but I would think it's because that back when the compound was being developed was the era when Indian drug patents did not exist. As the country has entered the WTO, it's had to comply with the world's intellectual property framework, and it's safe the say that the dust has not yet settled from this process.

So when Novartis filed for an imatinib patent in India, it was for a different polymorph of the drug, which they hoped would be patentable chemical matter. The Indian patent office disagreed in 2006, saying that this was merely a reformulation of an existing compound (which had been approved in the US back in 2001), and rejected the application. Novartis has been appealing that decision through the Indian court system ever since, and this latest ruling is the last, from the Indian Supreme Court. As the court's decision says:

In the application it claimed that the invented product, the beta crystal form of Imatinib Mesylate, has (i) more beneficial flow properties: (ii) better thermodynamic stability; and (iii) lower hygroscopicity than the alpha crystal form of Imatinib Mesylate. It further claimed that the aforesaid properties makes the invented product “new” (and superior!) as it “stores better and is easier to process”; has “better processability of themethanesulfonic acid addition salt of a compound of formula I”, and has a “further advantage for processing and storing.”

Novartis, for its part, feels that they have been done in by one particular section of Indian patent law, section 3(d). This was put in to prevent companies from "evergreening" their drug patent estates, and it requires proof of enhanced efficacy for new forms of existing compounds in order for them to be patentable. (That's as opposed to the situation in most other patent regimes, where once you've shown that you have a new substance, the uses you already knew about for its earlier form are enough to establish utility, to go along with the novelty). Here's Novartis' take:

Glivec has been awarded patents in nearly 40 other countries, including China, Russia and Taiwan, but the IPAB is denying one for India. The IPAB acknowledges that Glivec satisfies the international requirements for novelty and inventiveness, but it does not find Glivec to meet the requirement under Section 3(d) of the Indian Patents Act of 2005. This act introduced a new efficacy enhancement hurdle for patenting new forms of known compounds. We believe that Section 3(d), the Indian legal paragraph intended as a hurdle for evergreening, should not be applicable to the breakthrough medicine Glivec, which has changed the lives of patients with rare cancers.

The misconception regarding the innovation of Glivec is based on a patent that was granted in 1993 (not in India) for the synthesis of the molecule imatinib. This molecule, without further development, could not safely be administered to patients and represented only the first step in the process to develop Glivec as a viable treatment for cancer. We selected the mesylate salt of imatinib and then developed the beta crystal form of imatinib mesylate to make it suitable for patients to take in a pill form that would deliver consistent, safe and effective levels of medicine.

Novartis claimed that the increased bioavailability qualified as increased efficacy, but the opposing argument was that therapeutically, the two compound forms were never shown to be differentiated. The Indian Supreme Court, in fact, noted in its decision that Novartis had never provided any data on the effect of bioavailability on therapeutic efficacy, with the implication being, I think, that if they had such data they surely would have presented it by now in order to strengthen their case. The court had this to say about the beta-crystalline form:

It is seen above that in the US the drug Gleevec came to the market in 2001. It is beyond doubt that what was marketed then was Imatinib Mesylate and not the subject product, Imatinib Mesylate in beta crystal form. It is also seen above that even while the appellant’s application for grant of patent lay in the “mailbox” awaiting amendments in the law of patent in India, the appellant was granted Exclusive Marketing Rights on November 10,2003, following which Gleevec was marketed in India as well. On its package, the drug was described as “Imatinib Mesylate Tablets 100 mg” and it was further stated that “each film coated tablet contains: 100 mg Imatinib (as Mesylate)”. On the package there is no reference at all to Imatinib Mesylate in beta crystalline form. What appears, therefore, is that what was sold as Gleevec was Imatinib Mesylate and not the subject product, the beta crystalline form of Imatinib Mesylate.

I'm of two minds about that argument. The packaging often does not describe individual polymorphs of compounds - both the original form of imatinib and the beta-crystalline form are properly described as "imatinib mesylate". At the same time, it does appear that the drug has been administered as the earlier form for some time. So the Indian court affirms their section 3(d), which is a high bar, but they do say that it should be one that is clearable in practice:

We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment.”

We'll have to see how this works out in practice. India has a right, of course, to set its patent laws out in this way, but will it always work out like this when a section 3(d) issue comes up again? Or will that only be when it's a multinational company selling an expensive drug? Pricing, in fact, is not supposed to enter into this dispute, although for a while, it looked as if it would. The Indian appellate board, as Spicy IP reports, had originally tried to being in another interesting part of the patent law, section 3(b), which forbids patents for inventions that "offend public order or morality". They had tried the argument that Novartis' pricing offended public morality, but the Indian Supreme Court, to their credit, declined to pursue that line of thought.

So this case is not the end of drug patents in India. It's not supposed to be some mighty victory for the generic drug makers there, either, although I'm sure they're happy with it. (I might note that all the preening in the Indian press about the country being the "pharmacy to the world" would be more justified if any of the drugs being made had actually been discovered in India, through the ingenuity of Indian drug companies, risking Indian capital and shareholders' money. But they weren't).

What it does mean is that Indian drug patent law has gone from being nonexistent a few years ago, to being one of the strictest around. I hope that it's applied uniformly. Novartis has lost what was not a very strong case, to be honest, but the courts in India will hear stronger at some point.

These court rulings always inspire mixed feelings. On one hand they do make important drugs available to millions who cannot afford them, but they also damage a company's incentive to make profits and recuperate their R&D costs. In this case I don't think the loss in income is going to make more than a dent in Novartis's revenues, but it could set a troubling precedent for future cases.

To be fair they did call themselves the "pharmacy" of the world rather than the "pharmaceutical industry", so their role would be akin to a pharmacy's in terms of just dispensing drugs and not inventing them.

If Novartis wants to move R&D out of India, let them. It's not like they bring any value to any country's economy.. just a bunch of fishing expeditions cranking out incremental improvements to what's already available.

The larger indian population is poor and this can be said of the masses in all countries. Mostly these folks die without therapy. What is the use of innovation if people cannot afford it.

Even western nations cannot afford innovative dugs. but under the guise of innovation these drugs continue to be super-expensive. Gattex, kalydeco, juxtapid, kyprolis to name a few cost greater than $ 200K per year !!

It might be a mistake to read to much into this - as Derek points out, it is not an especially strong case. However, when you look at the new rules that India adopted last month for clinical trials, a pattern begins to emerge. Those rules, which hold sponsors completely responsible for anything that could happen to a patient, including, so help me, "Lack of effect of placebo", plus this ruling signals to me that India is trying to throw its weight around. Yes, it's a big market, but if companies can't make a profit, then you will see investment dry up fast.

the entry is correct that the original molecule (imatinib) predates the pharma product patent regime. But the salt form was also claimed in that patent too. So the 1993 patent on the API was not available in India. THis case was about a polymorph of the salt. See here for more discussion:http://www.sciencemag.org/content/337/6093/414.summary

This same legal issue prevents the patenting of new uses, so BG-12 (tecfidera) from Biogen Idec will not be patentable in India, unless the company finds another way. BG-12 is, we remember, nothing more than dimethyl fumarate, but in pharmaceutical form it sells for about $55,000 as a highly effective treatment for multiple sclerosis. It will be difficult for generic companies to file for this product in India without access to registration trial data, and commercially problematic for them to conduct their own trials without some form of market protection.

Regarding bringing expensive medicines to the masses.... This is hearsay (from a generally reliable source) and I have no way to independently prove it, but there was a lengthy piece about this issue this morning on the BBC World News Service. One thing that the Novartis spokesperson stated was that 95% of the patients receiving Gleevec in India were getting the drug for free. The remainder received some subsidy. The drug from the generic manufacturers is estimated to cost three times the average annual income. They had a lawyer on who was supporting the Indian position and she reiterated those numbers and did not dispute them.

If the above is only half correct then there remains the potential for many who are currently benefiting from the drug to be denied access in the future. That is unless the "big, bad, multinational drug company" continues to give the drug away for free or the generic manufacturers decide to pick up the load.

It's funny that novartis didn't show the efficacy to bioavailability/exposure relationship. I saw as one of the slides explaining the rationale for tasigna a slide showing that efficacy of Glivec correlated with plasma trough levels. So they had that data hiding somewhere in the company, in at least some form that might have hinted in the direction they wanted.

@medchemist: novartis is not doing any serious R&D in india. If you think they dont bring any economic value to any country, I dont know in what world you are living in. They are spending billions for R&D in US and China... not in India. sorry for them

It is possible that they may be more worried about generic material being exported than about lost revenue in India. The unpredictability associated with polymorphs might be invoked as a defense against a charge of lack of novelty.

Can someone clarify the "evergreening" issue for me? I was under the impression that the point of patenting a slightly modified drug was to make a slightly better drug, and therefore be able to claim an exclusive advantage over emerging generics that makes them non-equivalent. Then you can continue selling at a large price premium. Does the patent on the slightly modified drug actually legally prohibit others from selling the old drug that was disclosed decades ago?

@ Peter - remind me how much Apple earned in China last year as a %tage of sales ? Novartis and others may not even come close to getting back those billions of $s. Look outside your pigeon-hole once in a awhile.

Western countries subsidize the cost of drugs for other countries.
Who is going to be the generic manufacturer following this ruling? I'm betting it isn't a Swiss company. I'm betting it is a company from India.

Western countries also subsidize most of the academic research.

What we pay out of our paychecks, at the pharmacy, and through our tax dollars is very philanthropic. I think many in those countries do not believe that.

18: Yes, poorer countries benefit from western drug research that is mostly paid for by westerners. The same could be said for military research, or agriculture research, or advances in computers, or...

I don't really see the problem. The US has lots of rich sick people (or sick people with insurance) who are able to shell out a lot for new drugs. India doesn't. Americans are willing to pay these high prices regardless of whether Indians can buy the drugs cheaper or not. It's a classic case of price discrimination: those who are willing to pay more are charged more. And I don't really think there's anything too wrong with that. In the end drug companies make the majority of their profits in the U.S. (which has enough sick people to continue to drive new discoveries), but poor people in other parts of the world still get to benefit from the new advances.

Derek: could you clarify why drug pricing is usually not part of patent disputes such as this? Most media coverage alleges that there is almost an order of magnitude difference in the price per patient per dose of Gleevec and generic versions.

Also, having had a US patent (and in other countries) for Gleevec for such a long time, isn't it conceivable that the R&D costs have in fact been recovered?

I think one good way to understand the reasoning behind the court decision is to read it carefully, especially paragraph 189 where the court claims that "No material has been offered to indicate that the beta crystalline form of imatinib will produce an enhanced or superior efficacy (therapeutic) on molecular basis than what could be achieved with imatinib free base in vivo animal models" http://supremecourtofindia.nic.in/outtoday/patent.pdf

So the question is: is this statement correct? Is the ß-Crystalline form of imatinib not used in the marketed product today? Is there a difference in bioavailabilty between Imatinib mesylate and the polymorph crystal?

Another AP (4/1) story reports, "Major drugmakers such as Pfizer and Bayer AG on Monday declined to say what they might do regarding the ruling and other recent decisions by poor countries to let local drugmakers sell cheap generic versions for medicines that have monopolies under patents in Western countries. ... One thing is clear, though: Emerging markets are not the gold mine that optimistic pharmaceutical executives have been making them out to be."

a different and previosly not described polymorph is not exaclty a "slighltly modified" product. Different polymorphs *can* have dramatically different bioavailbilty (and this is a serious issue , with generics).

Patenting new polymorphs used to be the way to go to extend life of "tired" compounds. Now, regulations seems to get tighter and the requirements to be fulfilled are not only the "novelty" in general sense. You got to demonstrate that you are "solving a problem" with the new polymorphic form (eg. bioavailability or shelf-life, hygroscopicity... all things which are impacting formulations !!).

The question is: what's the market calling for) old polymorph or beta-form? So why not producing the old polymorph and market that? Looks to me that the beta-form is actually need for some formulation problems. any thought from you on that?

Patenting new polymorphs used to be the way to go to extend life of "tired" compounds. Now, regulations seems to get tighter and the requirements to be fulfilled are not only the "novelty" in general sense. You got to demonstrate that you are "solving a problem" with the new polymorphic form (eg. bioavailability or shelf-life, hygroscopicity... all things which are impacting formulations !!).

The question is: what's the market calling for) old polymorph or beta-form? So why not producing the old polymorph and market that? Looks to me that the beta-form is actually need for some formulation problems. any thought from you on that?